The purpose of this grant is to continue the studies on the mechanism of insulin antagonism in obesity, infection and uremia and to ascertain whether growth hormone acts as an insulin antagonist by stimulating the oxidation of fatty acids (FA) in muscle at the expense of glucose. Obesity - Previous studies have not documented insulin insensitivity of the enlarged fat cell, but pharmacological concentrations of insulin and dietary factors may account for this. Therefore, dose-response curves with physiological concentrations of insulin will be performed on adipose tissue from obese and lean subjects to overcome the first objection and the insulin in response of small and large cells from the same subject will be assessed to overcome the second objection. If insulin insensitivity of the large fat cell can be demonstrated, the site of this antagonism will be elucidated by measuring insulin binding, glucose transport and phosphorylation and glycolytic intermediates. Infection - Previous studies on a rat model for chronic pyelonephritis have demonstrated impaired glucose and insulin tolerance and a blunted insulin effect on hepatic gluconeogenesis. Carbohydrate metabolism in chronic infection will be further evaluated in liver slices by measuring glucose conversion to CO2, lactate, lipids and glycogen and the effect of insulin on the pathways of glycogen and lipid synthesis will be assessed. (These two pathways are stimulated by insulin in liver slices from normal rats in our laboratory). Uremia - The hypothesis that low protein intake of uremics causes abnormal growth hormone (GH) secretion which, in turn, causes glucose intolerance will be tested. Exercise-stimulated GH responses and glucose tolerance will be measured under 4 conditions; before and after dialysis and on 30 and 70 gm protein diets. Growth hormone - GH will be injected into rats in a schedule that will cause abnormal glucose metabolism by muscle in vitro. Oxidation of free FA as well as tissue triglyceride and phospholipid FA will be measured in the same tissue. If fat oxidation is increased in tissue from GH-injected rats, muscle will than be incubated with bromostearate, an inhibitor of FA oxidation, which should normalize glucose.